Hematology – Fostering a Spirit of Innovation

May 2019

Automation will continue to grow in the hematology laboratory as the number of technologists continues to decrease. The need for today is to have sophisticated systems, where one can put samples on and only be available to look at those truly abnormal samples.

During the first half of the 20th century, the complete blood count (CBC) was performed using exclusively manual techniques. From a simple automated blood cell count, to the first seven-parameter CBC, experts saw hematology changing before their eyes. More reliable automated platelet counts were added in the 1970s. In the 1980s the industry saw the first hematology analyzers that could perform automated differentials and the first automated reticulocyte analyzers. In the late 1990s, the advent of digital cell images and automated manual differentials were witnessed. Today, modern automated cell counters sample blood, and quantify, classify, and describe cell populations. Progressive improvement in these instruments has allowed the enumeration and evaluation of blood cells with great accuracy, precision, and speed, at a very low cost per test. Nowadays, analyzers can accomplish more and more routine diagnostics, and the role of the hematology technologist continues to evolve and expand.

Nevertheless, a number of technological solutions have been developed for laboratory hematology in recent times. These basically include commercialization of modular, high-throughput, and versatile analyzers, which can be easily interconnected by means of sample conveyers, and can fit the organization of small, medium, and large facilities; integration of preanalytical workstations, which can be identical to those included in models of total laboratory automation, or can be specifically designed to suit hematological testing; connection with automated slide strainers, which help improving the entire slide-making process (i.e., less manual activities and lower biological risk, improved standardization of slide preparation and staining, customization of staining protocols, reduction of TAT); and integration of automated image analysis systems.

Automation will continue to grow in the hematology laboratory as the number of technologists continues to decrease. The need for today is to have sophisticated systems, where one can put samples on and only be available to look at those truly abnormal samples. The ability to automate for walk-away systems to improve productivity is a big area. However, hematology is becoming a very competitive market, and sometimes pricing rather than best-available technology influences the purchasing of the analyzers.

Indian market

The Indian hematology instruments and reagents market in 2018 is estimated as Rs 790 crore. Reagents constitute 63.3 percent of the market at Rs 500 crore, and instruments the balance at Rs 290 crore.

The hematology instruments market may be segmented as 5-part and 3-part analyzers. By quantity, in 2018, the 3-part analyzers dominated with an estimated 85 percent market share, albeit the margins continued to come from the 5-part analyzers. Within the 3-part analyzer segment, the single-chamber is a dying breed and the laboratories are opting for its double-chamber counterpart. Within the 5-part analyzers, the entry-level analyzers are more popular. The maximum growth is being seen by the 5-part entry-level analyzers.

In April 2019, Sysmex reinforced direct sales and support network in India to expand its hematology business. By offering direct sales and support, the company aims to foster direct customer communications, enabling it to provide solutions to the diverse issues customers face. This approach should also allow Sysmex to step up its activities involving scientific seminars – an area of strength – as part of its aim to be a comprehensive supplier in India.

Since Sysmex selected Transasia Bio-Medicals Ltd. as its Indian distributor in 1993, the two companies have worked together to expand sales and support networks in India. In 1998, Sysmex established a joint venture with Transasia Bio-Medicals (now, Sysmex India) and began manufacturing reagents. In 2007, the company established a reagent factory in Baddi, and in 2008 Sysmex converted the company to a wholly owned subsidiary. In this manner, Sysmex established a business base in India, centered on the field of hematology, and promoted sales and support through local distributors.

Sysmex plans to work with its current distributor to ensure a smooth transition for all its customers in India. Going forward, Sysmex aims to strengthen its sales and support network and provide Sysmex support services as it strives to contribute to the development of healthcare.

Just recently, Transasia has introduced its latest range of 3- and 5-part fully automated hematology analyzers, which have been developed at Erba Europe, the global R&D facility of Transasia. These instruments are set to provide affordable diagnosis to cater to the masses.

At the buyer end, consolidation is inevitable. A case study of Neuberg Diagnostics sets the trend. Neuberg, which has 60 diagnostic labs and close to 500 collection centers in India, is planning to set up 40 more labs across the country with an investment of Rs 200 crore. Most of the investment will be done through internal accruals, and by its partners. The company wants to decentralize its reference lab model and have localized presence for advanced tests in proteomics, metabolomics, and genomics. The five labs that are now under Neuberg are Anand Diagnostic Laboratory, Supratech Micropath, Ehrlich Lab, Global Labs, and Minerva Labs, present in Karnataka, Gujarat, Tamil Nadu, South Africa, and UAE respectively. Neuberg has three global reference laboratories located in Bangalore, Ahmedabad, and Durban (South Africa).

Key players active in the hematology analyzer market are introducing new and innovative products to maintain or increase their market share. In addition, several companies are manufacturing and marketing miniature instruments with high accuracy. Analyzers are converging multi-parameter tests into single platforms through these miniaturized instruments, thereby helping labs and hospitals to save on heavy investments.

In March 2019, the Everstone Group, via its healthcare platform Everlife, acquired a stake in Chennai-based CPC Diagnostics to include core in vitro diagnostic segments in its portfolio of medical devices and extend its geographical presence to India, with this first investment in the country. Everlife also has investments in Malaysia-based Chemopharm Group, a leading provider of products and solutions to laboratory, research and medical facilities in South-East Asia; DV Medika Group, manufacturer and distributor of one of Indonesia’s top brands of hospital furniture and other imported medical equipment and supplies; and Singapore-based Bio-REV Pte. Ltd., which specializes in distribution of reagents, media, and consumables to the life sciences industry.

In March 2019, DxH 520 hematology analyzer from Beckman Coulter received 510(k) clearance from the US Food and Drug Administration (FDA). Designed for low-volume laboratories, including clinics and physician offices, the DxH 520 features unique technology that improves sample flagging by 40 percent, ensuring better first-pass yield and accurate differentials with as little as 17 microliters of blood.

In February, 2019, Horiba Medical introduced malaria screening and routine hematology. Based on the innovative data mining techniques combined with full blood count, the malaria-suspicion flag is optionally available on both the ABX Pentra XL 80 and Pentra XLR.

Global market

The global hematology analyzers and reagents market was valued at USD 3.23 billion in 2018 and is expected to generate revenue of around USD 5.09 billion by the end of 2024, growing at a CAGR of 7.90 percent, projects Zion Market Research. Improvements in analytical capabilities, rise in demand for analyzers with lesser operator intervention, increase in demand for point-of-care (PoC) analyzers, growing compatibility with electronic medical record system, and rising innovation are anticipated to propel the global market. Moreover, rapidly increasing number of hospitals and diagnostic laboratories due to surging prevalence of chronic diseases, cancer, vector-borne diseases, and blood disorders have been driving the market growth. In addition, rising geriatric population, increasing global healthcare expenditure, and technological advancements in medical research
have been contributing in the market growth of hematology analyzers, and this trend is expected to continue in the years to come.

The rising demand for blood banks is one of the critical reasons that will drive hematology analyzers and reagents market growth. Blood banks are witnessing a huge outflow of blood units to hospitals and other end users and inflow of blood units from blood donations on a daily basis. Hematology analyzers are extensively used in several screening tests. This results in an increased need for hematology analyzers and reagents for blood quantification.

Additionally, the rising usage of automated systems, such as automated hematology analyzer systems, will also drive hematology analyzers and reagents market growth. The use of automated hematology analyzers improves laboratory productivity by minimizing human error. It also generates precise results and offers faster turnaround time with superior performance optimization, resulting in reduced overall cost of diagnostic tests. As a result, there is a rising demand for these automated systems, especially in conducting reticulocyte analysis and coagulation tests. The advent of PoC hematology testing devices has led to improved diagnostics and patient outcomes. These devices are user friendly and are available for use outside the hospital settings. This is anticipated to increase the acceptability and accessibility of hematology testing which, in turn, is anticipated to propel market growth.

Product recall and intense market competition, leading to price wars, hinder market growth. In 2018, Becton Dickinson (BD) and Company recalled Vacutainer EDTA blood collection tubes owing to chemical interference with certain tests. This recall was classified as Class-I recall, the most serious type of recall, by the US Food and Drug Administration (FDA), thereby indicating that the use of these devices may cause serious injuries or death. Such product recalls negatively affect market growth.

The instruments segment held a major share of the hematology analyzers and reagents market owing to the growing demand for these instruments from the end users. The increasing adoption rate of the automated hematology instruments, along with the growing demand for highly sensitive hematology testing, is likely to drive the market for instruments segment in the coming years. Also, rising developments in high-end technology, like the introduction of basic cytometry techniques analyzers and the expansion of high throughput hematology analyzers, have been propelling industry growth.

The hospitals and diagnostic centers segment will account for the highest hematology analyzers and reagents market share. The growing demand for hematology analyzers and reagents in hospitals and outpatient transfusion centers, because of the prevalence of certain conditions, such as hemophilia and cancer that necessitate regular blood transfusions through transfusion therapy, will drive market growth in this end-user segment.

Regionally, North America will account for the largest hematology analyzers and reagents market. Increasing investments in healthcare research and testing in hematology in the US, rising healthcare awareness among the population, and increase in a number of highly advanced diagnostic clinics are some of the major reasons for the high growth of the market in this region. Asia-Pacific is projected to witness swift growth during 2019–2024 owing to the rising healthcare expenditure, coupled with focus on quality healthcare infrastructure.

While procuring a hematology analyzer, buyers take into consideration:

Sample size and micro-sampling the facility will be handling;

Range of tests to be carried out;

Kind of reagents that will be required and where to source them;

The accuracy, precision, and linearity of the device;

Degree of automation of the analyzer and its processes;

Total time per analysis;

Enquire about maintenance, calibration, and quality control;

Check how to analyze results analysis and store samples; and

Ask if there will be any footprint (digital/radioactive).

Technology trends

Innovative erythrocyte parameters. Irrespective of the fact that the diagnosis of anemia is relatively simple and straightforward (by measuring total hemoglobin in whole blood), the newer generation of hematologic analyzers is now equipped with many analytical and technical innovations, which enable obtaining other information than that reported with the traditional complete blood cell count, and which may ultimately provide a substantial improvement for the differential diagnosis of anemias. These innovative parameters most typically include automated reticulocyte and nucleated RBC counts, hemoglobinization of reticulocytes and RBC, reticulocyte hemoglobin content (occasionally defined as CHr and RET-He according to the technology used for its assessment), reticulocyte maturation, automatic analysis, and calculation of microcytic and hypochromic RBC. The various combinations of these different parameters not only may be useful to complement clinical history, physical examination and results of more conventional laboratory investigations (i.e., CBC, ferritin, transferrin, iron, haptoglobin, folic acid, and vitamin B12, among others) for troubleshooting the underlying cause(s) of anemia, but may also be clinically useful for diagnosing, prognosticating, and monitoring other non-RBC disorders. The generation of complex scattergrams, which is now almost commonplace in the vast majority of hematologic analyzers, is also helpful for more accurately identifying abnormal RBC populations and other atypical elements.

Disruptive technologies. Regardless of consolidated laboratory techniques, which have just recently made their way through phenotypic diagnostics of anemia (i.e., capillary electrophoresis), a major innovation has been represented by the application of mass spectrometry and molecular biology in the diagnostics of hemoglobinopathies. The former approach allows a better characterization of hemoglobin variants preliminarily identified by screening techniques, such as high-pressure liquid chromatography or capillary electrophoresis, whilst molecular diagnostic techniques enable to unravel specific molecular abnormalities characterizing many congenital RBC disorders.

Unlike screening tests, the selection of the most appropriate molecular diagnostic approach in patients with inherited hemoglobinopathies or RBC enzymopathies should take into account the prevalence and penetrance of the different mutations in the ethnic populations, across different geographical locations. Therefore, the first step may be represented by polymerase chain reaction (PCR)-based techniques [e.g., restriction-endonuclease PCR (RE-PCR), amplification refractory mutation system (ARMS), resolution melting analysis (HRMA), and denaturing gradient gel electrophoresis (DGGE)]. Allele-specific methodologies, such as allele-specific PCR and reverse dot-blot, are especially useful for thalassemia diagnostics in target populations, enable processing a high volume of samples, and are relatively inexpensive, permitting to screen some prevalent hemoglobin genes mutations at the same time. Array comparative genomic hybridization (array CGH) can then be used for detecting additional mutations, which cannot be identified with first-line DNA analysis. Regarding thalassemia, gap-PCR (gap-PCR) and multiplex ligation-dependent probe amplification (MLPA) are perhaps the best options for screening and also for detecting large deletions or duplications of globin genes, which cannot be identified with conventional DNA sequencing. Sanger or next-generation sequencing (NGS) techniques may then be particularly suited for detecting all known point-mutations, but may also enable identifying novel or rare mutations, thus helping to uncover new mechanisms of disease. A reliable guidance for the cost-effective integration of these different molecular techniques has recently been published by the European Molecular Genetics Quality Network (EMQN). Notably, emerging evidence also suggests that molecular genetic testing has a pivotal role in patients with diseases characterized by clonal hematopoiesis, thus supporting the diagnostic workout of hematologic malignancies and/or myelodysplastic syndromes.

Digital hematology. Recent technological advances have led to development and commercialization of innovative automated image-analysis systems, which are suited for automation and can hence be directly connected (in series) with hematologic analyzers. These innovative platforms scan the slides (usually at a picture of ×100 objective), and store digitized images of blood smears at high magnification. The images are analyzed by artificial neural networks, based on a preexisting database of blood elements (thus including RBC), which can be locally customized or updated by the users. The images can be transmitted to, and displayed on, computer screens, which can be even placed at long distances from the scanner (i.e., in hospital wards or in remote laboratories), for analysis and potential reclassification of blood elements. The operator can also increase the size of the images, or expand single sections of the scan, so obtaining a more accurate view. The operator can then accept and conserve the automatic classification, or can move elements from one cell category to another, thus improving the final reclassification. Albeit these automated image-analysis systems have been originally developed for analysis of white blood cells (WBC), specific information can also be garnered on erythrocyte morphology, thus including the presence of anysocytosis, hypochromia, microcytosis or macrocytosis, spherocytosis, elliptocytosis, ovalocytosis, stomatocytosis, acanthocytosis, echinocytosis, polychromasia, poikilocytosis and abnormal erythrocytes (i.e., sickle cells and schizocytes, helmet and teardrop cells). Recent data showed that the diagnostic sensitivity of these systems for identifying some critical categories of abnormal erythrocytes is excellent, typically higher than 80 percent, thus making the use of digital image analysis a highly valuable, and probably more accurate and reproducible, alternative to optical microscopy. Notably, the use of these systems may also enable an efficient recognition of parasitoid infections, such as malaria, as well as the reliable identification of intravascular and spurious hemolysis, which would be otherwise undetectable on whole blood specimens. Interestingly, most of these automated image-analysis systems are also capable of optimizing the identification of rare RBC abnormalities, since morphological erythrocyte alterations can be more efficiently visualized on the computer screen. Finally, the creation of a large personalized database of images of suggestive RBC abnormalities represents a valuable resource for education and training of students and laboratory professionals.

Way forward

The many technological advances occurred in laboratory medicine over recent times have enabled the introduction of a vast array of innovations, which have led the way to a more efficient patient care and a more convenient organization of resources and workflows within the laboratory. In the foreseeable future, the better understanding of phenotypic heterogeneity of RBC disorders, also supported by IT tools, such as expert diagnostic systems or artificial neural networks, will predictably enable to improve the global management of these disorders at multiple levels. Yet, some additional issues will need to be addressed, on top of it all the current lack of harmonization in laboratory hematology.